Corneal Crosslinking Review PDF

Review Article – Narrative Review Taiwan J Ophthalmol 2024;14:44‑49 Access this article online Quick Response Code: A comprehensive review on corneal crosslinking...

Review Article – Narrative Review Taiwan J Ophthalmol 2024;14:44‑49 Access this article online Quick Response Code: A comprehensive review on corneal crosslinking Andrea Naranjo, Edward E. Manche* Website: Abstract: http://journals.lww.com/TJOP Corneal crosslinking (CXL) represents a paradigm shift in the management of corneal ectatic disorders. DOI: Before CXL was introduced, patients would need specialty contact lenses and possible corneal 10.4103/tjo.TJO-D-23-00055 transplantation. CXL involves a biochemical reaction in which ultraviolet A light is used in conjunction with Riboflavin to form crosslinks in between corneal stromal collagen. This leads to strengthening and stabilizing of the collagen lamellae, resulting in mechanical stiffening of the cornea. Multiple protocols have been proposed including epithelium on versus off and varying light intensity and duration of treatment. All protocols appear to be safe and effective with few reported complications including infection, stromal haze, scarring, and endothelial toxicity. Overall, CXL has demonstrated to halt the progression of the disease clinically and in keratometry readings and improve the quality of life for patients. It is a minimally invasive, cost‑effective procedure that can be performed in an outpatient setting with a fast recovery time and long‑lasting results. Keywords: Cornea, cross‑linking, ectasia, keratoconus, riboflavin Introduction through crosslinking using UV light and riboflavin. C rosslinking is the process of forming chemical bridges between proteins and other molecules. Corneal Mechanism of Action crosslinking (CXL) naturally occurs CXL is a complex biochemical reaction in in the cornea by a reaction between which photo‑oxidation occurs between UVA transglutaminase and lysyl oxidase. This light and Riboflavin. This photochemical glycosylated crosslinking is responsible for process occurs in an aerobic and an anaerobic increasing corneal stiffness with age. phase. Riboflavin molecules absorb UVA light and gets excited to a triplet state. During Riboflavin, also known as Vitamin B2, is a the aerobic phase (Type II photochemical micronutrient important for maintaining process), the excited triplet riboflavin healthy tissues. When exposed to ultraviolet interacts with oxygen in the atmosphere A (UVA) radiation, riboflavin molecules and forms reactive oxygen species including Department of absorb energy and reach an excited state. In its singlet oxygen. This singlet oxygen reacts Ophthalmology, The Byers Eye Institute, Stanford excited state, riboflavin it can either produce with the collagen carbonyl groups, creating University School of radicals or singlet oxygen species.[3,4] These new bonds between the aminoacids and Medicine, Palo Alto, active molecules can induce covalent bonds collagen molecules. During the anaerobic California, USA and therefore crosslink molecules. Since phase (Type I photochemical mechanism), Address for 1970, investigators reported crosslinking the triplet riboflavin transfers electrons correspondence: reactions in collagen and elastin. However, or hydrogen ions and forms riboflavin Dr. Edward E. Manche, it was in 1997 that Spoerl et al. used this radicals. Both the radicals and the singlet The Byers Eye Institute, principle to increase corneal stiffness Stanford University School oxygen specials will increase the formation of Medicine, Palo Alto, This is an open access journal, and articles are of covalent crosslinks in between corneal California, USA. distributed under the terms of the Creative Commons stromal collagen. This increases the E‑mail: cornea@ Attribution‑NonCommercial‑ShareAlike 4.0 License, which stanford.edu allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and How to cite this article: Naranjo A, Manche EE. Submission: 17‑04‑2023 A comprehensive review on corneal crosslinking. Accepted: 01‑09‑2023 the new creations are licensed under the identical terms. Taiwan J Ophthalmol 2024;14:44-9. Published: 02-02-2024 For reprints contact: [email protected] 44 © 2024 Taiwan J Ophthalmol | Published by Wolters Kluwer - Medknow strength of the cornea by increasing the diameter of the irradiation dose of 5.4 J/cm2. A meta‑analysis performed crosslinked Type I collagen fibers. comparing regular Dresden protocol with accelerated CXL, demonstrated standard CXL had a greater effect The effect of crosslinking collagen fibers leads to in terms of reduction in Kmax than accelerated CXL; strengthening and stabilizing the collagen lamellae, however, accelerated CXL had less effect on central resulting in mechanical stiffening of the cornea. This in corneal thickness and endothelial cell loss. Multiple turn has been shown to improve corneal curvature that studies have shown no significant difference between can be evidenced with keratometric and topographical conventional and accelerated CXL regarding the parameters. uncorrected, best‑corrected visual acuity (BCVA), and refractive outcome following treatment. In addition, crosslinking collagen fibers have also been shown to induce a high resistance to enzymatic Another proposed CXL protocol is pulsed CXL. digestion. This is important for many corneal disease Proponents state this may increase oxygen delivery processes as collagen degradation secondary to enzyme to the cornea during treatment. Specially, during the degradation (Typsin‑2 and cathepsin K within the tear aerobic phase that occurs during the first 10–15 s of film) has been associated to thinning in keratoconus (KC) continuous UVA illumination of a riboflavin‑soaked and corneal melting secondary to enzyme degradation cornea. Pulsating UVA radiation can lead to higher can be seen in cases of infectious keratitis. oxygen concentrations and therefore promoting an increase in the Type II photochemical mechanism. Types of Crosslinking When compared to the conventional protocol, pulsed light treatment seems to be able to possibly penetrate Dresden protocol versus accelerated corneal deeper in the corneal stroma, with a similar efficacy and crosslinking versus pulsed corneal crosslinking safety profile. The standard of treatment is based on the Dresden protocol that was described by Wollensak et al. in Epithelium‑on versus epithelium‑off crosslinking 2003 as a treatment option for KC. This technique is The Dresden protocol removes the epithelium to increase done under topical anesthesia and involves removing the amount of riboflavin absorption into the cornea. the central corneal epithelium (9 mm) by mechanical The epithelium can be removed mechanically with a debridement, followed by the application of riboflavin blunt hockey knife, blunt spatula, rotating brush, by solution (0.1% riboflavin in 20% dextran solution) to the simply wiping off the epithelium with or without the de‑epithelialized cornea for 30 min. The de‑epithelized use of alcohol or by transpithelial phototherapeutic cornea soaked in riboflavin is afterward exposed to UVA keratectomy. De‑epithelizing the cornea can lead light (370 nm) under a power of, 3 mW/cm2 (5.4 J/cm2) for to complications including corneal haze and pain. 30 min. Riboflavin solution is continuously applied every Transepithelial CXL or Epi‑on is a newer option to 2–5 min during this irradiation process.[11,12] Usually, promote faster healing, less patient discomfort, faster antibiotic drops are then administered postoperatively, visual rehabilitation, and less risk of corneal haze. and a bandage contact lens is placed for pain control. Nonetheless, the epithelium essentially works as a barrier and thus decreases riboflavin penetration and oxygen To ensure an adequate corneal depth is obtained for availability. the treatment in thin corneas, ultrasound pachymetry can be performed during initial Riboflavin instillation. Stulting et al. conducted a large prospective study in If the cornea is thinner than 400 µm, then hypotonic which 512 eyes of 308 patients with KC and 80 eyes of riboflavin ophthalmic solution without dextran can be 55 patients with postlaser in situ keratomileusis (LASIK) administered after which ultrasound pachymetry can ectasia were treated with trans‑epithelium CXL using a be rechecked until a minimum of 400 µm is obtained. proprietary transepithelial riboflavin formulation. Two hundred and twenty‑nine were bilateral treatments. One issue with the Dresden protocol is the long treatment VA improved by 1–1.5 Snellen lines at 1 and 2 years duration time. According to Bunsen‑Roscoe’s law of postoperatively (P < 0.0001) and mean Kmax decreased reciprocity, the same photochemical effect should by 0.48 D at 2 years postoperatively (P = 0.0002). They be obtained with a reduced illumination time if the demonstrated no progression of ectasia and persistence correspondingly irradiation intensity is increased. of this effect at 1 and 2 years postoperatively, no vision Therefore, multiple protocols have been attempted with threatening events and VA returning to baseline within higher intensity of light to decrease the amount of 2 days with pain typically resolving within 24 h. These exposure time. Accelerated CXL uses a higher intensity results demonstrated epithelium‑on CXL could be used light of 30, 18, or 9 mW/cm2 during a shorter amount to halt KC and post‑LASIK ectasia in a safer and faster of time 3, 5, or 10 min, respectively, for a cumulative manner. Taiwan J Ophthalmol - Volume 14, Issue 1, January-March 2024 45 Nonetheless, there have been multiple studies comparing other hand, the control group showed a continuous these two techniques. A Cochrane systemic review deterioration in Kmax and BCVA. determined that no conclusion can be obtained between these methodologies given the lack of precision, frequent Although further studies must be performed, CXL indeterminate or high risk of bias, and inconsistency is generally considered in cases of progressive KC. in methods and outcomes among studies. Further Progression is determined by was defined as one or more randomized, prospective studies are warranted to of the following changes over a period of 24 months: An determine the superiority in efficacy or safety between increase of 1.0 D or greater in the steepest keratometry epithelium on versus epithelium off CXL. measurement, an increase of 1.0 D or greater in manifest cylinder, or an increase of 0.5 D or greater in manifest New emerging corneal crosslinking methods refraction spherical equivalent. Based on the same photochemical process, a variety of dyes have been studied. Recently, the spotlight has been Corneal ectasia on Rose Bengal (RB) dye excited with green light. It has Corneal ectasias are a known complication of refractive been shown to increase corneal stiffness while having surgery. This can occur following both LASIK, less cytotoxic effect in the deeper layers of the cornea.[21‑23] photorefractive keratectomy, and small incision lenticule This could be a promising treatment for thin corneas that extraction. Attempting to prevent this, both prophylactic are not candidates for CXL. Similarly, photosynthetic CXL as well as simultaneous treatment has been pigments (chlorophylls and bacteriochlorophylls) proposed. Even though corneal stiffness improves cases introduced into rabbit corneas were excited with of corneal ectasia, there appears to be less response to CXL near‑infrared illumination with resulting increase in in patients with postrefractive surgery ectasia compared corneal stiffness. to KC. Pellucid marginal degeneration (PMD) is another indication of CXL. Interestingly, PMD is thought Applications to affect the peripheral cornea and CXL usually has its effect on the central cornea. Keratoconus KC is a spontaneous corneal ectasia that usually affects Corneal crosslinking in the pediatric population the younger population, and it is estimated to have The effectiveness of the CXL in the pediatric population an incidence of 1 in 2000. Vision is usually impaired is still a matter of debate. While some studies have because of the irregular astigmatism of the cornea. shown an improvement of keratometric values with This is usually corrected with rigid gas permeable a reduction in the progression of the disease within lenses or scleral contact lenses during the initial the age group of 9–18 years, others illustrate adverse stages. Penetrating keratoplasty is considered the outcomes such as worsening of corneal thickness and gold standard when refractive correction is no longer topography values.[33-35] One of the largest studies was possible due to severe irregular astigmatism, corneal the Siena Pediatrics CXL study. It was a prospective, scarring, or previous rupture of the Descemet membrane. nonrandomized study conducted on 152 KC patients Depending on the case, some patients can be candidates between 10 and 18 years of age. This study reported for lamellar keratoplasties including deep anterior significant and rapid functional improvement in lamellar keratoplasty, anterior lamellar keratoplasty, or pediatric patients younger than 18 years with progressive intrastromal corneal ring segment. KC and KC stability at the 36‑month follow‑up. CXL halts KC progression by strengthening and Pain is another factor that must be considered in the stabilizing the collagen lamellae, resulting in corneal pediatric population. In a large, prospective epithelium‑on mechanical stiffening. This can reduce the irregular CXL study, 26 eyes of patients 18 years of age or younger astigmatism caused by corneal chemical instability and were evaluated at 12 months after epithelium‑on CXL therefore improve refractive errors while also avoiding for KC. There was a significant improvement in best further corneal steepening. Keratometry readings corrected VA, high‑order aberrations, Kmax and evidence demonstrate a flattening in Kmax as well as improvement of no disease progression. Hence, epithelium‑on CXL in ocular aberrations after crosslinking. could be a more appropriate treatment for the pediatric population in an attempt to decrease pain related to A randomized, controlled clinical trial of CXL versus epithelium‑off CXL. control in KC, randomized 66 eyes of 49 progressive KCN patients into CXL treatment and control groups. Considering most of pediatric cases will progress, with At the 1‑year follow‑up, Kmax had been significantly some cases even having “accelerated” progression as reduced, with an average decrease of 1.45 diopters well as the risk of needing a penetrating keratoplasty and improvement in BCVA was also observed. On the in this population, some ophthalmologists argue that 46 Taiwan J Ophthalmol - Volume 14, Issue 1, January-March 2024 CXL should be performed immediately after diagnosis is corneal collagen stroma during CXL would make made. While others believe not all children need CXL water filling more difficult and therefore decrease and documentation of progression should exist before the amount of corneal edema. Studies demonstrated deciding to perform CXL. Given stabilization and bullous keratopathy markedly improved after CXL, possible improvement of visual and corneal parameters unfortunately, these effects disappeared about 3 months in a generally well‑tolerated procedure. CXL is after the initial CXL treatment. becoming common practice in this population. Contraindications Infectious keratitis CXL has also been used to treat severe, multidrug‑resistant Thin corneas corneal ulcers.[39,40] The antimicrobial effects of riboflavin Since the beginning of the procedure until 1–3 months and UVA light in conjunction to the increase resistance after treatment, CXL causes corneal thinning. The to enzymatic degradation, which prevents corneal corneal thickness starts improving after 3 months melting, makes CXL a very attractive option for resistant and recovers until getting to baseline by 12 months. infectious keratitis. Nonetheless, in thin corneas, this immediate decrease in corneal thickness can lead to endothelial damage. Unfortunately, results have been controversial. CXL As such, according to the Dresden protocol, a minimum has been shown to be an efficient treatment stabilizing of 400 µm corneal thickness is required to be suitable advanced melting corneal ulcers and to be useful in early for CXL. infectious keratitis of bacterial origin. A meta‑analysis demonstrated an 88% healing rate in bacterial keratitis Prior herpetic infection with CXL but did not show to be effective in cases of Herpetic keratitis may be triggered by CXL, even in viral keratitis and the procedure has exacerbated corneal cases with no history of the disease. Even though melting in some cases. In addition, it has been reported prophylactic systemic antiviral treatment in patients to have poor response to fungal and acanthamoebic with a history of the herpetic might decrease the infections. This is probably because of how deep these possibility of recurrence, CXL should be avoided in infections get into the corneal stroma.[42,43] A study these patients. comparing CXL for infectious keratitis versus standard antibiotic treatment in Egypt, Iran, and Thailand between Other 2010 and 2014, demonstrated there is not enough evidence Severe corneal scarring, neurotrophic keratopathy, past that CXL with standard antibiotics is more effective than history of poor epithelial wound healing, severe dry eye, standard antibiotics alone for complete healing. autoimmune disorders, and pregnancy are currently considered contraindication for CXL. Interestingly, Rose Bengal coupled with green light appears to have a more promising antimicrobial effect. Complications An in vitro experiment comparing the effect of RB and riboflavin as photosensitizing agents for photodynamic Corneal infection therapy on Fusarium solani, Aspergillus fumigatus, and De‑epithelization during epi‑off techniques as well as Candida albicans demonstrated Rose Bengal Photodynamic bandage contact lens placement predisposes patients Therapy (RB-PDAT) successfully inhibited the growth of to corneal infections. Even though infection following all three fungal isolates in the irradiated area, whereas transepithelial treatment is usually rare, infectious riboflavin‑mediated photodynamic therapy (PDT) did keratitis following CXL has been reported in all not have any inhibitory effect on the isolates. Initial approaches. Bacterial, acanthamoebic, herpetic, and clinical experiments with RB‑PDAT as a last resource fungal infections have all been reported.[5,53] As bacterial for infectious keratitis with different etiologies (bacterial, infections are the most common, routine antibiotic drops fungal, and parasitic) demonstrated the therapy was able are given for prophylaxis following treatment. to avoid a therapeutic keratoplasty in 72% of the cases and could therefore be considered as an adjunct therapy Endothelial toxicity for cases of severe, progressive infectious keratitis. CXL causes corneal keratocytes apoptosis and cell These results appear to persist in a longer‑term follow‑up shrinkage of the anterior corneal stroma reaching a and the crosslinking effect appears to increase graft corneal tissue depth of 250–300 µm. These keratocytes survival at 1 year postoperatively. repopulate within 3 months and CXL is therefore considered safe as the depth of apoptosis would not Other (bullous keratopathy and corneal burns) affect the corneal endothelium. Nonetheless, direct CXL has been proposed as a possible treatment for UVA irradiation can harm the corneal endothelium and bullous keratopathy. The links created between the if the cornea is initially thinner or if it thins excessively Taiwan J Ophthalmol - Volume 14, Issue 1, January-March 2024 47 during the procedure, there is a potential risk of Financial support and sponsorship endothelial toxicity following CXL. Nil. Stromal haze and scarring Conflicts of interest The most common reported adverse event following The authors declare that there are no conflicts of interests CXL is stromal haze. This adverse effect can be clinically of this paper. significant and can affect VA. 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